1. Field of the Invention
The present invention relates to a therapeutic agent for cancers intended to activate natural killer T (NKT) cells, to a method of screening such a therapeutic agent and to health-care auxiliary food preparations for oral uptake which are taken up with view to obtaining anti-cancer activity intended to activate NKT cells.
2. Description of the Related Art
Screening of substances useful for the prevention or therapy of cancers has been made laying importance on their direct action onto cancer cells. It has been known that immune activators are useful in the therapy of cancers. However, the compounds obtained as immune activators are all weak in their anti-cancer effect and no sufficient therapeutic effect against cancers has been achieved yet by immune therapy alone or even by immune therapy in combination with chemical therapy.
Dr. Yagita, the inventor of the present invention, paid attention to the usefulness of substances that induce interleukin 12 (IL-12) in vivo and found that AHCC, a processed product of the mycelia of Lentinus edodes (Berk.) Sing. (also called shiitake), has such a function as above and established a method of treating cancers, i.e., a new immunological therapeutic method. IL-12 itself is known to have an anti-cancer effect but cause side effects when administered directly to patients and the patients tend to be intolerable to the therapy. Therefore, IL-12 itself could hardly be used as an anti-cancer agent. However, the preparation containing AHCC which Dr. Yagita reported has achieved remarkable curing and life lengthening effects in the therapy of cancers. In other words, Dr. Yagita has achieved an object of treating cancers by administration of an effective amount for inducing IL-12 in vivo of AHCC (JP 10-139670A).
IL-12 has an activity of increasing production of interferon xcex3 (IFN-xcex3), an activity of activating and enhancing natural killer (NK) cells, lymphokine activated killer (LAK) cells, and killer T cells, which are competent for cell mediated immunity. INF-xcex3 is a cytokine that induces an immune response of an organism in a state where T helper 1 (Th1) is active. In this state, NKT cells or killer T cells readily exhibit their effects and in other words production of interleukin 2 (IL-2) and IL-12 occurs on a large scale. Killer T cells and LAK cells are known to be cells that participate in cancer immunity. NK cells are also reported to participate in anti-cancer activity of an organism. In the case of NK cells, Dr. Yagita proved that the clinical anti-cancer effect and their activity do not correlate with each other and the amount of induced production of IL-12 and NK activity show a complete inverse correlation therebetween. Therefore, it is concluded that no NK cell participates in anti-cancer activity in humans.
Currently, Dr. Yagita has indicated that a substance that has activity of inducing the production of IL-12 is likely to be a promising carcinostatic substance.
However, in some patients who suffer cancers, the administration of AHCC does not sufficiently induce the production of IL-12 to give no therapeutic effect or even when it induces the production of IL-12, it gives no sufficient therapeutic effect. Accordingly, there has been a keen demand for the development of a novel therapeutic agent for cancers which agent acts in a mechanism other than the anti-cancer effect which AHCC has.
It has been known that in the mechanism of cancer immunity, the amount of cytokine produced or induced in vivo is an important factor and hence a therapeutic method has been proposed and practiced which administers, induces or cause to be produced a cytokine that is believed to have anti-cancer activity to treat the cancer. However, although the relationships between cancers and immunity or between cancers and cytokines have been made clearer, the effect of curing the cancers and of life lengthening have been observed in 50% or less of patients who suffer the cancers. Furthermore, recently, natural killer T (NKT) cells have been found as cells that participate in cancer immunity (Cui J. et al., Science 278, 1623, 1997). The NKT cell is one of various types of cells that participate in the immune system and has, for example, potent cytokine productivity, in particular IFN-xcex3 productivity, and a function of cytotoxicity through Fas or perforin. Therefore, it is anticipated that activation of the cells will further increase curing or life lengthening effects in those patients who suffer cancers.
Taniguchi et al., have found a specific glycolipid antigen. This antigen is recognized by specific T cell antigen receptor (TCR), Vxcex124Vxcex211, that NKT cells have. Taniguchi et al. reported that the antigen is an xcex1-galactosylceramide. Furthermore, Taniguchi et al. proved that in cancer-carrying mice administered with (xcex1-galactosylceramide, NKT cells are activated and metastasis of the cancer is suppressed though the elimination of cancer is not observed.
It has been reported that NKT cells contain NK cell antigen receptor (hereinafter, sometimes referred to also NKR-P1; natural killer receptor P1) as another receptor (Special issue: Basis and Clinic of NKT Cells; Saishin Igaku (Current Medicine), Vol. 55, No. 4, 2000, p. 818-823). NKR-P1 also participates in the activation of NKT cells.
An object of the present invention is to elucidate the mechanism of activating NKT cells and provide a novel and useful therapeutic agent for cancers having an ability of activating NKT cells.
With view to solving the above problems, the present inventor has made extensive research on cancer immunity cascade for the prevention or therapy of cancers and as a result he has found that in the cascade in which activated NKT cells competent for cancer immunity participate, two different antigen receptors, i.e., NKR-P1 and Vxcex124Vxcex211 have quite different activities from each other. The present invention has been achieved based on this discovery.
That is, the present invention provides the followings:
(1) A therapeutic agent for a cancer comprising a therapeutically effective amount of an active ingredient, wherein the therapeutic agent is used referring to an ability of acting on natural killer receptor P1 of natural killer T cell as an index of the ability to activate the natural killer T cell.
(2) The therapeutic agent for a cancer as described in (1) above, wherein the active ingredient comprises a substance having a capability of selectively acting on natural killer receptor P1 of natural killer T cell to activate the natural killer T cell.
(3) The therapeutic agent for a cancer as described in (2) above, wherein the active ingredient comprises at least one substance selected from products derived from the mycelia of fungi having an ability of selectively acting on natural killer receptor P1 of natural killer T cell to activate the natural killer T cell.
(4) The therapeutic agent for a cancer as described in (2) above, wherein the substance in the active ingredient comprises at least one selected from polysaccharides derived from the filtrate of culture of the mycelium of Shizophyllum commune Fries, processed products of the mycelium of Coriolus versicolor (Fr.) Quel., and processed product of the mycelium of Shiitake.
(5) The therapeutic agent for a cancer as described in (4) above, wherein the substance in the active ingredient comprises a sugar component having xcex1-1,3-glucoside linkage structure.
(6) The therapeutic agent for a cancer as described in (1) above, wherein the agent comprises a processed product of the mycelium of Shizophyllum commune Fries or a polysaccharide derived from the filtrate of a culture of the mycelium of Shizophyllum commune Fries, a processed product of the mycelium of Shiitake, and a processed product of the mycelium of Ganoderma lucidum (Fr.) Karst.
(7) The therapeutic agent for a cancer as described in (1) above, wherein the agent comprises 20 to 60% by weight of a processed product of the mycelium of Shizophyllum commune Fries or a polysaccharide derived from the filtrate of a culture of the mycelium of Shizophyllum commune Fries, 20 to 60% by weight of a processed product of the mycelium of Shiitake, and 5 to 40% by weight of a processed product of the mycelium of Ganoderma lucidum (Fr.) Karst.
(8) The therapeutic agent for a cancer as described in (1) above, wherein the agent comprises 30 to 50% by weight of a processed product of the mycelium of Shizophyllum commune Fries or a polysaccharide derived from the filtrate of a culture of the mycelium of Shizophyllum commune Fries, 30 to 50% by weight of a processed product of the mycelium of Shiitake, and 10 to 30% by weight of a processed product of the mycelium of Ganoderma lucidum (Fr.) Karst.
(9) The therapeutic agent for a cancer as described in (1) above, wherein the agent is in the form of a formulation suitable for oral administration.
(10) The therapeutic agent for a cancer as described in (1) above, wherein the therapeutic agent selectively acts on natural killer receptor P1.
(11) The therapeutic agent for a cancer as described in (1) above, wherein the therapeutic agent induces mass production of interferon xcex3 as a result of selective action on natural killer receptor P1 and shifts the ratio of T helper 1 cell/T helper 2 cell, Th1/Th2, toward a value at which an immune system where mainly Th1 acts operates.
(12) The therapeutic agent for a cancer as described in (1) above, wherein natural killer receptor P1 is determined by measuring CD3 and CD161, cell surface markers, and the ability of activating natural killer T cell.
(13) A method for screening therapeutic agents for a cancer, comprising screening a therapeutic agent for a cancer based on an ability of acting on natural killer receptor P1 of natural killer T cell as an index of the ability to activate the natural killer T cell.
(14) The therapeutic agent for a cancer as described in (1) above, wherein it is used as a health-care auxiliary food preparation for oral uptake.
(15) A method of treating a cancer, comprising administering to a patient suffering a cancer a therapeutically effective amount of an active ingredient, said agent being used referring to an ability of acting on natural killer receptor P1 of natural killer T cell as an index of the ability to activate the natural killer T cell.
(16) A health-care auxiliary food comprising a substance having a capability of selectively acting on natural killer receptor P1 of natural killer T cell to activate the natural killer T cell.
(17) A commercial medium carrying information as described in (1) above.
(18) A commercial method utilizing information as described in (1) above.